Multiple sclerosis (MS) is an autoimmune disease causing neurological deficits associated with inflammation- mediated damage to myelin sheaths covering brain and spinal cord neurons. Axonal damage is now believed to occur early in the disease course, in every new lesion, with progressive and irreversible disability arising from cumulative axonal loss. The autoimmune attack on the central nervous system (CNS) in MS has been suggested to be a secondary pathogenic factor evoked by CNS injury. Autoimmunity against myelin antigens further exacerbates the autocatalytic process of neurodegeneration. The approach proposed herein aims to combine the two necessary components of MS therapeutic approaches into a single strategy addressing the dendritic cell (DC) phenotype imbalance and promotion of neuroprotection. The overall goal is elucidate the biomaterial and immunological basis of a biomaterial strategy for immunomodulation through MS-antigen specific immunosuppressive DC delivery within a polyethylene glycol (PEG) hydrogel and combined with delivery of the neuroprotective factor, neuregulin-1 (NRG-1), to ameliorate the murine experimental autoimmune encephalomyelitis (EAE) model of MS. The hypothesis for this research is that DCs, rendered antigen specific and tolerogenic by contact with an MS antigen upon immunosuppressive molecule treatment in vitro, can be applied to the cervical lymph nodes (cLNs), using a localized hydrogel system, along with release of the neuroprotective agent, NRG-1, to ameliorate EAE disease outcomes through immunomodulation and neuroprotection. In this study, a simplified biomaterial strategy, with demonstrated efficacy as described in the preliminary results, is based on the delivery of immunosuppressive MS antigen-specific murine DCs to the neck location of mice within an in situ gelling PEG hydrogel, minimally modified to present the cell adhesion peptide, RGD. Two specific aims are proposed: 1) demonstrate functionality of critical components of the assembled multifunctional biomaterial for delivery of immunosuppressive, MS antigen-specific DCs and NRG-1; and 2) elucidate efficacy of the multifunctional biomaterial for amelioration of murine EAE through immunomodulation and neuroprotection and identify critical construct components.